Earnest efforts to develop transdermal drug delivery devices that provide drug to the patient in a controlled pattern began in the late 1960s and early 1970s. The principal pattern of delivery that was investigated was substantially constant rate delivery in which delivery began at or shortly after the device was applied to the skin, rose to a desired level, and stayed at that level for a sustained time period. These efforts resulted in numerous patents being issued for devices of various structures that achieved or closely mimicked constant rate delivery. See, for instance, U.S. Pat. Nos. 3,598,122; 3,598,123; 3,797,494; and 4,286,592.
Nitroglycerin (NTG) is among the many drugs that has been administered transdermally. Among the U.S. patents describing transdermal NTG delivery are U.S. Pat. Nos. 3,742,951; 4,533,540; 4,559,222; 4,618,699; 4,681,584; 4,654,209; 4,655,766; 4,661,441; 4,751,087; 4,776,850;, 4,778,678; 4,784,857; and 4,786,282. None of these patents concern delayed onset nitroglycerin delivery. Further, the initial commercial transdermal NTG devices (the Transderm-Nitro and Nitro-Dur devices) are continuous rather than delayed-onset delivery devices.
In the mid-1980s a number of clinical studies raised questions about the efficacy of NTG therapy provided by the then available commercial transdermal devices that administered NTG in a continuous pattern. Specifically, continuous administration was tending to cause tolerance and hemodynamic attenuation. This led clinicians to conclude that the ideal regimen for administering NTG would include an overnight "washout period" during which no NTG was administered. Correlatively, it led developers of transdermal devices to propose delayed onset devices for administering NTG.
U.S. Pat. No. 4,956,181 describes a delayed onset device for administering NTG. Its device consists of a backing layer, a rupturable pod sandwiched between the backing and a nonwoven fabric layer, a barrier membrane, an adhesive layer, and a release liner. The rupturable pod contains NTG and an activator liquid that is capable of plasticizing the barrier membrane and increasing its permeability to NTG. Once the pod is ruptured, drug and activator migrate down through the barrier membrane, with the activator causing the membrane to become increasingly permeable to the drug. While this patent indicates that an effective delay of up to 12 hr may be achieved, the examples of the patent describe devices that achieve only a 4-6 hr delay.
An object of the present invention is to provide a delayed onset device for administering NTG that provides at least a six and preferably an eight hour delay in administration. The device of the invention does not use plasticization of a barrier membrane as a delay mechanism.